UA72541C2 - A pharmaceutical composition containing benzamide derivative - Google Patents

Abstract

There are provided pharmaceutical formulations with improved oral absorptivity and injections that contain, as active ingredients, high concentrations of benzamide derivatives and their pharmaceutically acceptable salts, which are useful as histone deacetylase inhibitors. A pharmaceutical solution is prepared by dissolving a benzamide derivative or a phannaceutically acceptable salt thereof in an organic solvent and/or acidic liquid, and a pharmaceutical formulation is prepared by adding a surfactant, an acidic substance and/or a polyethylene glycol. The present invention has enabled dissolution of benzamide derivatives or their phannaceutically acceptable salts at high concentrations, to prepare practical injections and oral liquid formulations and improve absorptivity with oral administration.

Description

itself polysorbate 80;

MY Pharmaceutical composition according to (9), in which the carbohydrate ester is an ester of sucrose and a fatty acid;

M12Y Pharmaceutical composition according to any of I51-I11Y, in which the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid;

A pharmaceutical composition according to any one of (51-11), wherein the carboxylic acid is citric acid, fumaric acid, adipic acid, tartaric acid, malic acid or acetic acid; 14 Pharmaceutical composition according to any of (I5II17Y), in which the sulfonic acid is aminoethylsulfonic acid;

І5І Pharmaceutical composition according to any of І|5І-І11|І, in which the acidic polysaccharide is alginic acid;

I16Y Pharmaceutical composition according to any of (51-11), in which the acidic amino acid is aspartic acid or glutamic acid; (17) The pharmaceutical composition according to any one of (51-11), wherein the salt of the amino acid and the inorganic acid is glycine hydrochloride, aspartate hydrochloride or glutamate hydrochloride.

Figure 1 shows the dependence of concentrations (compound 1) in plasma upon oral administration of the compositions obtained in examples 2-4 and comparative example 1 to unfed male hound dogs, together with 20 ml of water.

This invention will be explained in more detail below. Compositions are mainly prepared by adding one or more additives and an active ingredient.

Derivatives of benzamide, which play the role of active ingredients of the compositions under consideration, represented according to the invention by formula (1), are shown in Table 1.

Table 1 (0) s | yo: one MN of the 1st year of the MN

M

(e) (c) s» shchy MN MN.

Compound 2 | And about MN

M

0) (c) si he Mo

Compound Z r MN

M o)

These compounds can be prepared as described in Japanese Published Application NO! Me10-152462, which did not pass the examination.

Surfactants to be used in the present invention include anionic surfactants, cationic surfactants, nonionic surfactants, amphoteric surfactants, and others without particular limitations; sodium lauryl sulfate, polysorbate 80, sucrose fatty acid ester, etc. Mostly they are used either by themselves or in combination with each other.

Acidulants to be used in the present invention include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, di-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethylsulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and salts of amino acids with inorganic acids, such as glycine hydrochloride, aspartate hydrochloride, and glutamate hydrochloride.

One or more acidulants may be used in the present invention.

These acidulants may be combined with the active ingredient and with surfactants, organic solvents, polyethylene glycol and/or other additives, but all must be used as an aqueous solution.

Organic solvents used in the present invention include methanol, ethanol, propylene glycol, glycerol, dimethylformamide and propylene carbonate, and one or all of them need not necessarily be used as a solution in water.

The polyethylene glycol used in the present invention is not particularly limited in terms of its molecular weight, but preferably the molecular weight should be in the range of 200 to 20,000, and more preferably 200 to 600. One type or more may be selected for use, depending on necessarily - in the form of an aqueous solution.

A soft capsule with an encapsulated liquid in it, a hard capsule with an encapsulated liquid in it, etc., according to this invention, can be obtained by dissolving an appropriate amount of a benzamide derivative or its pharmaceutically acceptable salt, () in a liquid containing one or more substances of a group consisting of organic solvents, polyethylene glycols and surface-active substances (surfactants); (ii) in a liquid containing water and one or more substances from the group consisting of organic solvents, polyethylene glycols and surfactants; (ii) in a liquid that contains one or more acidifiers, water and one or more substances from the group consisting of organic solvents, polyethylene glycols and surfactants; or (them) in a liquid containing one or more acidulants and water, and making a soft capsule containing a liquid inside, a hard capsule containing a liquid inside, or the like by means of conventional methods well known to those skilled in the art in this field.

The organic solvent used in the manufacture of soft capsules, hard capsules, etc., includes methanol, ethanol, propylene glycol, glycerin, dimethylformamide and propylene carbonate; polyethylene glycol used in the manufacture of soft capsules, hard capsules, etc., includes polyethylene glycols with a molecular weight of 200 to 600. Surfactants used in the manufacture of soft capsules, hard capsules, etc., include polysorbate 80; and the acidulant used in the manufacture of soft capsules, hard capsules, etc., includes inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethylsulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and amino acid salts with an inorganic acid, such as glycine hydrochloride, aspartate hydrochloride, and glutamate hydrochloride.

According to the invention, solid compositions, for example, powder, granules, tablets, pills and capsules can be made by adding to the active ingredient one or more substances selected from the group consisting of surface-active substances, such as sodium lauryl sulfate and sucrose fatty acid ester , polyethylene glycol, for example, polyethylene glycol 4000 and polyethylene glycol 6000; acidifiers, which include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, di-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethylsulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and salts of amino acids with an inorganic acid, such as glycine hydrochloride, aspartate hydrochloride, and glutamate hydrochloride, followed by use in the manufacturing process of an inert filler, binder, disintegrant, lubricant, coating agent, etc., in accordance with conventional methods known to those skilled in the art.

Inert excipients used in the present invention include SO-mannitol, lactose, sucrose, corn starch, crystalline cellulose, and the like. Binders used in the present invention include hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, glycerin, water, and the like.

Disintegrants used in the present invention include carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, and the like.

Lubricants used in the present invention include magnesium stearate, calcium stearate, and the like.

Coating agents used in the present invention include hydroxypropylmethylcellulose, methacrylic acid copolymers, hydroxypropylmethylcellulose phthalate, and the like.

Tablets can be core-coated tablets, if necessary, for example, sugar-coated tablets; tablets encapsulated in gelatin; tablets covered with a film stable in the intestinal environment; or film-coated tablets. In addition, the tablets may consist of allegedly two layers or several layers, when there are separate layers of the active ingredient, acidifier, surfactant, etc. in them.

The injection solution according to the present invention can be obtained by dissolving an appropriate amount of a benzamide derivative or its pharmaceutically acceptable salt () in a liquid containing one or more substances from the group consisting of organic solvents, polyethylene glycols and surface-active substances ( South Africa); (ii) in a liquid containing water and one or more substances from the group consisting of organic solvents, polyethylene glycols and surfactants; (ii) in a liquid that contains one or more acidifiers, water and one or more substances from the group consisting of organic solvents, polyethylene glycols and surfactants; or (them) in a liquid containing one or more acidifiers and water, and manufacturing injection forms using conventional methods well known to those skilled in the art.

The organic solvent used in the manufacture of injection forms includes methanol, ethanol, propylene glycol, glycerin, dimethylformamide and propylene carbonate; polyethylene glycol, which is used in the manufacture of injection forms, includes polyethylene glycols with a molecular weight of 200 to 600. Surfactant, which is used in the manufacture of injection forms, includes polysorbate 80; and the acidifier used in the manufacture of injection forms includes inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid,

maleic acid, dI-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethylsulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and amino acid salts with an inorganic acid, such as glycine hydrochloride, aspartate hydrochloride, and glutamate hydrochloride.

Alternatively, after dissolving in water one or more substances selected from the group consisting of these acidifying substances, an appropriate amount of the benzamide derivative or a pharmaceutically acceptable salt thereof can be dissolved using a method known to those skilled in the art.

In this case, surfactants such as sodium lauryl sulfate and/or sucrose fatty acid ester and/or polyethylene glycol such as polyethylene glycol 4000 and/or polyethylene glycol 6000 may be used together to improve the solubility of the benzamide derivative.

There are no special restrictions on the method of administration of the pharmaceutical composition according to the present invention, and this composition can be administered by a method suitable for the given dosage form, age, gender and degree of severity of the condition and other circumstances. For example, tablets, pills, liquid medicines, syrups, suspensions, emulsions, granules and capsules are administered orally, while injections are given intravenously either by themselves or mixed with a conventional liquid form containing glucose, amino acid, etc.; if necessary, they are administered intramuscularly, subcutaneously or intraperitoneally.

Doses of these pharmaceutical compositions according to the invention can be selected accordingly, based on the method of administration, age, gender and severity of the patient's condition and other factors; however, the dosage of the most active ingredients can be from about 0.0001 to 100 mg per kilogram of body weight. The amount of active ingredient per unit dosage form is preferably in the range of about 0.001 to 1000 µg.

EXAMPLES

The present invention will be further explained in detail with the help of examples and a comparative example. It should be noted, nevertheless, that the present invention should not be limited in any way to the given examples.

Example 1

After thoroughly shaking 100 mg of compound 1 with 1 mL of each of the following: 0.05 N hydrochloric acid, methanol, ethanol, propylene carbonate, polysorbate 80, polyethylene glycol 400, polyethylene glycol 300, glycerol, dimethylacetamide, or propylene glycol at room temperature, the supernatant obtained by centrifugation of each mixture is separated , and they use it as a pharmaceutical solution. Control samples for comparison are also prepared by thoroughly dissolving 1000 mg of compound 17 in 1 Oml of each of the following: purified water, sodium acetate buffer solution with pH 4.0, or sodium phosphate buffer solution with pH b.8 at room temperature, and separating the supernatant obtained as a result of centrifugation. Table 2 shows the result of measuring the concentration of compound 1 in each sample using HPLC.

All samples of this invention contained dissolved compound 1 at a concentration of 5 mg/ml or more, which is a sufficient concentration for injection. On the other hand, all comparative control samples contained dissolved compound 1 only at a concentration of 0.2 mg/ml or less, and thus the concentration required for injections could not be guaranteed.

Example 2 10.13g of PEG 400 and 1.08g of polysorbate 80 and 200mg of the compound | mixed together, the mixture is completely dissolved by ultrasonic treatment for 30 minutes with periodic stirring. For the manufacture of a pharmaceutical agent, hard gelatin capsules are filled with a solution in such a way that the dose can be 1.5 mg/kg based on the dog's body weight.

Table 2

Comparison of solubility of compound 1 in solvent

Compound tration (mg/ml) control examples

Neon PR acid 14.0 (methanol. 99

Samples according to the present invention

Example C

Weigh 200 mg of compound 1, 700 mg of polyethylene glycol 4000, 800 mg of polyethylene glycol 6000, 1200 mg of sodium lauryl sulfate and 1200 mg of sucrose fatty acid ester and mix in an agate mortar and grind with a pestle. To prepare a pharmaceutical agent, hard gelatin capsules are filled with well-ground powder in such a way that, before administration, the dosage is 1.5 mg/kg based on the dog's body weight.

Example 4

200 mg of compound 1, 1350 mg of glutamic acid hydrochloride and 1950 mg of O-mannitol are weighed, the mixture is stirred in an agate mortar and ground with a pestle. For the preparation of the pharmaceutical product, hard gelatin capsules are filled with the obtained powder in such a way that the dose can be 1.5 mg/kg based on the dog's body weight.

Comparative example 1

Weigh 200 mg of compound 1, 1000 mg of O-mannitol, stir the mixture in an agate mortar and grind with a pestle.

For the preparation of a pharmaceutical agent, the obtained powder mixture is filled into hard gelatin capsules in such a way that the dose can be 1.5 mg/kg based on the dog's body weight.

Example 5

An experiment on the assessment of solubility in water

The contents of each pharmaceutical composition obtained in Examples 2-4 and Comparative Example 1 were mixed with water and solubility was evaluated by measuring the concentration of compound 1 using

HPLC or observation of non-turbidity of color in the supernatant. Table C shows the results of the solubility determination based on measuring the concentration of compound 1 by HPLC or observing the non-turbidity of the color in each supernatant, then the content of each of the compositions obtained in examples 2-4 and comparative example 1 (the amount of compound 1 is 20 mg) , mixed with 1-1000 ml of purified water. According to the results of example 2, no precipitation of compound 1 was found in a mixture with water in any ratio. Regarding examples 3 and 4, it was found that the solubility was about 4 times greater and 100 times greater than in comparative example 1.

Table C

The solubility of each pharmaceutical composition in water is 0000 and water is

Example 2 0 | 0 1 Ш 0 | at

Example 3 | x | x | 0 | 0

Example 4. | x | 0 0 | o ve 1101 example 1 x x x

In the table, the symbol "x" means no dissolution of compound 1, and the symbol "0" means complete dissolution of compound 1.

Oral absorption test (oral absorption)

The pharmaceutical compositions obtained in examples 2-4 and comparative example 1 were administered orally to unfed male hound dogs in 20 ml of water.

Approximately 2.5 ml of blood was collected intravenously into a heparinized container at 15, 30, and 45 minutes and 1, 2, 4, 6, and 9 hours after administration, the blood was centrifuged, and plasma was collected. The active ingredient was isolated from plasma by liquid phase extraction and its concentration was determined by HPLC. The result is shown in Fig.1. In examples 2-4, the absorbance was higher than in comparative example 1.

Table 4 shows the pharmacokinetic characteristics upon oral administration of the pharmaceutical compositions obtained in examples 2-4 and comparative example 1 in 20 ml of water to unfed animals (male hound dogs). In examples 2-4, the AOC and Stach were higher than in comparative example 1, and the absorbability during oral administration was better.

Table 4

Pharmacokinetic characteristics for each pharmaceutical composition of example 1 0.31 0.25 0.42

The values shown in the table are average values, at n-3.

INDUSTRIAL SUITABILITY

Pharmaceutical solutions are prepared by dissolving the benzamide derivative or its pharmaceutically acceptable salt in organic solvents and/or acidifying liquids, and pharmaceutical compositions are prepared by adding surfactants, acidifiers and/or polyethylene glycols to the benzamide derivative or its pharmaceutically acceptable salt, thereby providing pharmaceutical compositions with a high degree of absorption (absorbability) when administered orally or by injection, containing as active ingredients benzamide derivatives or their pharmaceutically acceptable salts in high concentrations, which can be used as histone deacetylase inhibitors. 0.9 0.8 - in 07 sa; - 0.6 and sh 0 in same 03 -sh- EXAMPLE? 7 Z : shen EXAMPLE Z

IN 02 ND --- PCRIKLADY sh what -k- DIFFERENT EXAMPLE in 04 Хх

Zh -k o day N m 00 at 2 and 5 8 70

TIME (HOURS)

FIG. 1